FSD1 inhibits glioblastoma diffuse infiltration through restriction of HDAC6-mediated microtubule deacetylation

• DOI: 10.1007/s11427-024-2616-7
• Publication Date: 2025-01-14T04:49:37Z
• Authors: Dake Xiao; Haowen Ran; Lishu Chen; Yuanyuan Li; Yan Cai; Songyang Zhang; Qinghui Qi; Huiran Wu; Cheng Zhang; Shuailiang Cao; Lanjuan Mi; Haohao Huang; Ji Qi; Qiuying Han; Haiqing Tu; Huiyan Li; Tao Zhou; Fangye Li; Ailing Li; Jianghong Man
• Keywords: HDAC6; Infiltration (HVAC)

The infiltration of glioblastoma multiforme (GBM) is predominantly characterized by diffuse spread, contributing significantly to therapy resistance and recurrence GBM. In this study, we reveal that microtubule deacetylation, mediated through the downregulation fibronectin type III SPRY domain-containing 1 (FSD1), plays a pivotal role in promoting GBM infiltration. FSD1 directly interacts with histone deacetylase 6 (HDAC6) at its second catalytic domain, thereby impeding activity on α-tubulin preventing deacetylation depolymerization. This inhibitory interaction disrupted upon phosphorylation Ser317 Ser324 residues activated CDK5, leading dissociation from microtubules facilitating HDAC6-mediated deacetylation. Furthermore, increased expression or interference reduces suppresses invasion stem cells, ultimately mitigates tumor orthotopic xenografts. Importantly, tissues exhibit diminished levels expression, correlating unfavorable clinical outcomes patients. These findings elucidate mechanistic involvement driving cell offer potential avenues for managing